Regulation of T cell afferent lymphatic migration by targeting LTβR-mediated non-classical NFκB signaling

Lymphotoxin-beta receptor (LT beta R) signaling in lymphatic endothelial cells (LEC) regulates leukocyte afferent lymphatic transendothelial migration (TEM). The function of individual signaling pathways for different leukocyte subsets is currently unknown. Here, we show that LT beta R signals predominantly via the constitutive and ligand-driven non-classical NIK pathway. Targeting LT beta R-NIK by an LT beta R-derived decoy peptide (nciLT) suppresses the production of chemokines CCL21 and CXCL12, and enhances the expression of classical NF kappa B-driven VCAM-1 and integrin beta 4 to retain T cells on LEC and precludes T cell and dendritic cell TEM. nciLT inhibits contact hypersensitivity (CHS) at both the sensitization and elicitation stages, likely by inhibiting leukocyte migration. By contrast, targeting LT beta R-classical NF kappa B signaling during the elicitation and resolution stages attenuates CHS, possibly by promoting leukocyte egress. These findings demonstrate the importance of LT beta R signaling in leukocyte migration and LEC and lymphatic vessel function, and show that antagonist peptides may serve as lead compounds for therapeutic applications.